Transcriptional regulation of the 26S proteasome by Nrf1

Abstract

The 26S proteasome is a large protease complex that selectively degrades ubiquitinated proteins. It comprises 33 distinct subunits, each of which differ in function and structure, and which cannot be substituted by the other subunits. Owing to its complicated structure, the biogenesis of the 26S proteasome is elaborately regulated at the transcription, translation, and molecular assembly levels. Recent studies revealed that Nrf1 (NFE2L1) is a transcription factor that upregulates the expression of all the proteasome subunit genes in a concerted manner, especially during proteasome impairment in mammalian cells. In this review, we summarize current knowledge regarding the transcriptional regulation of the proteasome and recent findings concerning the regulation of Nrf1 transcription activity.

Keywords: DDI2; Nrf1; proteasome; transcription.

Figure 1.

Molecular architecture of the eukaryotic proteasome. The 26S proteasome is composed of the 20S core particle (CP) and one or two 19S regulatory particles (RP) attached to the CP terminus. The CP is a stack of four heteroheptameric rings consisting of two outer α-rings and two inner β-rings, each composed of seven structurally similar α- (α1–7) and β-subunits (β1–7), of which β1/2/5 contain proteolytic active sites exposed to the interior cavity of the CP (red circles). The RP is subdivided into the base and lid subcomplexes. The base is composed of an ATPase-ring that contains six AAA⁺ ATPase (Rpt1–6) and four non-ATPase subunits (Rpn1/2/10/13). The lid is composed of nine non-ATPase subunits (Rpn3/5/6/7/8/9/11/12/15).

Figure 2.

Domain organization of CNC-bZIP family proteins. The image depicts the domain organization of six human CNC-bZIP proteins, namely, Nrf1, Nrf2, Nrf3, NF-E2 (p45 subunit), Bach1, and Bach2. All these proteins share cap ‘n’ collar (CNC) and a basic leucine zipper (bZIP) domains in their C-terminus region. Nrf1, Nrf2, Nrf3, and NF-E2 p45 contain one or two acidic domains (AD1, AD2, or AD2L) and regulate the transcriptional activation. In contrast, Bach1 and Bach2 are known as transcription repressors without acidic domains. However, they contain a broad-complex, tramtrack, bric-a-brac (BTB) domain. Nrf1 and Nrf3 exhibit a N-terminal domain (NTD) with a transmembrane region to anchor proteins to the ER membrane. Additionally, Nrf1 and Nrf3 contain an Asn/Ser/Thr-rich (NST) domain, which is a target for N-glycosylation.

Figure 3.

ER and nuclear degradation of Nrf1 by the UPS. ER-anchored Nrf1 is degraded via ERAD machinery. The Nrf1 is ubiquitinated, retrotranslocated, and degraded by the ER-resident ubiquitin ligase Hrd1, p97, and the proteasome, respectively. In the nucleus, Nrf1 is ubiquitinated and degraded by nuclear localized ubiquitin ligases (β-TrCP and FBXW7) and the proteasome, respectively.

Figure 4.

Nrf1 activation pathway. Nrf1 is glycosylated in the ER. The glycosylated Nrf1 (denoted as G) is retrotranslocated by p97. In the cytosol, polysaccharides attached to Nrf1 are removed by NGLY1 to generate the full-length Nrf1 (F). Then, the aspartic protease DDI2 cleaves Nrf1 within the NTD domain and produces processed Nrf1 (P). Processed Nrf1 translocates from the ER into the nucleus and promotes the expression of targets including proteasome subunit genes.

Figure 5.

Regulation of Nrf1 transcription activity by phosphorylation and glycosylation. Nrf1 is phosphorylated by CK2 and GSK3β which decreases the transcription activity. PKC kinase activity is reported to enhance Nrf1 transcription activity; however, whether PKC phosphorylates Nrf1 directly remains unclear. Additionally, glycosylation status affects Nrf1 transcription activity. Nrf1 is N-glycosylated in the ER and deglycosylated by NGLY1 in the cytosol. The deglycosylation promotes Nrf1 transcription activity and processing by DDI2. The O-glycosylation of Nrf1 by OGT positively as well as negatively regulates Nrf1 activity.